Thermal injury and severe bleeding lead to shock. The acute therapeutic intervention is similar in both situations: primary treatment is fluid therapy. In the case of hemorrhagic shock, the lost blood volume must be replaced as quickly as possible. Initially lost blood volume is provided either by salt solutions, so called crystalloids, or with colloids, such as dextran or hydroxyethyl starch. If blood is available, the physician will replace lost blood by transfusion.
Burn injury is often accompanied by injury to the lungs caused by inhalation of hot and/or toxic substances, such as smoke, derived from combustion.
Severe burn injury affecting more than 15-20% of the total body area leads to tremendous loss of fluid through the burned skin and fluid replacement is an extremely important form of therapy for these patients. Both crystalloids and colloids are routinely used. Lung injury caused by smoke inhalation and other toxic fumes is also treated with fluids since the injury to the lung also causes loss of fluid.
The critical period of initial resuscitation, i.e. when fluid is administered, is the time when reperfusion injury occurs. During this period, which may be as short as a minute or as long as several hours, oxygen radical mediated injury appears to occur. Presently used volume expanders (crystalloids and colloids) do not provide the anti-oxidant properties necessary to mitigate such injury.
Deferoxamine (or desferrioxamine) and its pharmaceutically-acceptable salts are chelating agents. Deferoxamine mesylate is commercially available and is used to treat severe iron intoxication, iron storage disease or iron overload resulting from hemolysis due to drugs, thalassemia, sickle-cell anemia, frequent blood transfusions and the like.
There are a number of problems with the clinical use of deferoxamine mesylate. Since the drug is not appreciably absorbed when orally administered, it generally must be given parenterally. Once administered, the drug is very rapidly excreted. For example, in humans the drug is very rapidly excreted. For example, min. Chelation therapy with the drug, as a result, involves continuous infusion or frequent intramuscular injections, which may cause pain and/or induration at the injection site. Further, the acute and chronic toxicities of deferoxamine are relatively high, making the substance less versatile for therapeutic uses.
The substance deferoxamine is often abbreviated DFO or DES (not to be confused with diethylstilbesterol). For consistency, only the abbreviation DFO will be used herein. Terms such as "Dextran-DFO" mean an adduct of the polymer (dextran) with DFO. Such an adduct may include more than one DFO moiety per unit substrate.
EP-0 304 183A (corresponding to U.S. Pat. No. 4,863,964) discloses pharmaceutically acceptable water-soluble biopolymers covalently bonded to deferoxamine. Such biopolymers covalently bonded to deferoxamine are herein refused to as conjugates. Preferred conjugates consist of pharmaceutically acceptable water-soluble polysaccharides covalently bonded to deferoxamine, pharmaceutically acceptable water-soluble proteins covalently bonded to deferoxamine and water-soluble inulin-deferoxamine adducts.
It has now been discovered that such conjugates of deferoxamine are useful in fluid resuscitation.
It has also been discovered that DFO and water-soluble biopolymers even if not covalently bonded together may be useful in fluid resuscitation.